title: Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms.
abstract: Many genetic mouse models of Huntington's disease (HD) have established that mutant huntingtin (htt) accumulates in various subcellular regions to affect a variety of cellular functions, but whether and how synaptic mutant htt directly mediates HD neuropathology remains to be determined. We generated transgenic mice that selectively express mutant htt in the presynaptic terminals. Although it was not overexpressed, synaptic mutant htt caused age-dependent neurological symptoms and early death in mice as well as defects in synaptic neurotransmitter release. Mass spectrometry analysis of synaptic fractions and immunoprecipitation of synapsin-1 from HD CAG150 knockin mouse brains revealed that mutant htt binds to synapsin-1, a protein whose phosphorylation is critical for neurotransmitter release. We found that polyglutamine-expanded exon1 htt binds to the C-terminal region of synapsin-1 to reduce synapsin-1 phosphorylation. Our findings point to a critical role for synaptic htt in the neurological symptoms of HD, providing a new therapeutic target.
authors.affiliation: Department of Histology and Anatomy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China.
authors.forename: Qiaoqiao
authors.initials: Q
authors.lastname: Xu
authors.forename: Shanshan
authors.initials: S
authors.lastname: Huang
authors.forename: Mingke
authors.initials: M
authors.lastname: Song
authors.forename: Chuan-En
authors.initials: CE
authors.lastname: Wang
authors.forename: Sen
authors.initials: S
authors.lastname: Yan
authors.forename: Xudong
authors.initials: X
authors.lastname: Liu
authors.forename: Marta A
authors.initials: MA
authors.lastname: Gaertig
authors.forename: Shan Ping
authors.initials: SP
authors.lastname: Yu
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.forename: Shihua
authors.initials: S
authors.lastname: Li
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
mesh_terms: D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002853:Chromatography, Liquid; D004298:Dopamine / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000235:genetics; D010766:Phosphorylation; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016704:Synapsins / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics; D053719:Tandem Mass Spectrometry; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; D012333:RNA, Messenger; D016704:Synapsins; D050825:Synaptosomal-Associated Protein 25; C097188:polyglutamine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D004298:Dopamine